Experimental Research Center, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.
The Second School of Clinical Medicine , Zhejiang Chinese Medical University, Hangzhou, China.
Front Immunol. 2022 Jun 17;13:818120. doi: 10.3389/fimmu.2022.818120. eCollection 2022.
Clear cell renal cell carcinoma (ccRCC) is known for its high drug resistance. The tumor-immune crosstalk mediated by the epigenetic regulation of N6-methyladenosine (mA) modification has been demonstrated in recent studies. Therefore, mA modification-mediated immune cell infiltration characteristics may be helpful to guide immunotherapy for ccRCC.
This study comprehensively analyzed mA modifications using the clinical parameters, single-cell RNA sequencing data, and bulk RNA sequencing data from the TCGA-ccRC cohort and 13 external validation cohorts. A series of bioinformatic approaches were applied to construct an mA regulator prognostic risk score (MRPRS) to predict survival and immunotherapy response in ccRCC patients. Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low-MRPRS groups.
The expressional alteration landscape of mA regulators was profiled in ccRCC cell clusters and tissue. The 8 regulator genes with minimal lambda were integrated to build an MRPRS, and it was positively correlated with immunotherapeutic response in extent validation cohorts. The clinicopathological features and immune infiltration characteristics could be distinguished by the high- and low-MRPRS. Moreover, the MRPRS-mediated mutation pattern has an enhanced response to immune checkpoint blockade in the ccRCC and pan-cancer cohorts.
The proposed MRPRS is a promising biomarker to predict clinical outcomes and therapeutic responses in ccRCC patients.
透明细胞肾细胞癌（ccRCC）以其高耐药性而闻名。最近的研究表明，N6-甲基腺苷（mA）修饰的表观遗传调控介导的肿瘤-免疫串扰。因此，mA 修饰介导的免疫细胞浸润特征可能有助于指导 ccRCC 的免疫治疗。
本研究综合分析了 TCGA-ccRC 队列和 13 个外部验证队列的临床参数、单细胞 RNA 测序数据和批量 RNA 测序数据中的 mA 修饰。应用一系列生物信息学方法构建 mA 调节因子预后风险评分（MRPRS），以预测 ccRCC 患者的生存和免疫治疗反应。在高和低 MRPRS 组中评估了免疫特征、富集途径和突变。
mA 调节因子的表达改变景观在 ccRCC 细胞簇和组织中进行了分析。整合 8 个具有最小 lambda 的调节基因构建了一个 MRPRS，它与扩展验证队列中的免疫治疗反应呈正相关。高和低 MRPRS 可区分临床病理特征和免疫浸润特征。此外，MRPRS 介导的突变模式在 ccRCC 和泛癌队列中增强了对免疫检查点阻断的反应。
所提出的 MRPRS 是预测 ccRCC 患者临床结局和治疗反应的有前途的生物标志物。
